The University of Virginia School of Medicine currently has an obsolete 40-year-old orthovoltage XRAY machine which is used for irradiation of small animals. This proposal is to replace our obsolete irradiator with a state of the art small animal radiation research platform (SARRP) irradiator. In addition to delivering radiation in vitro, SARRP is the first system that integrates collimation, accurate dose modeling and 3D volumetric imaging guidance into a single platform thereby allowing highly conformal dose distributions to be achieved in animals. The SARRP provides an important tool in moving us to the era where small molecules, radiation, and immunotherapy are used synergistically. Radiation is the most active agent against most solid tumors. Recent improvements in radiation physics have led to dramatic improvements in radiation delivery, allowing elegant spatial targeting of the radiation dose. However, escalating spatially targeted doses has had only minimal impact on the local control rates of most solid tumors. One key advantage of radiation is that in contrast to essentially all chemotherapeutic and all molecular target agents, radiation does not induce resistance. Therefore, coupling spatially targeted radiation therapy with molecularly targeted agents designed to enhance tumor cell kill holds tremendous potential to improve local control rates of solid tumors. Indeed most patients treated in Radiation Oncology Departments for cure are treated with a combination of radiation and chemotherapy or molecularly targeted therapy. Identifying the optimal agents to use in combination with radiation as well as defining the mechanistic basis of drug/radiation interactions requires preclinical studies using focused radiation in order to mimic actual clinical treatments. The availability of an irradiator with these capabilities will stimulate such studies testing specific agents currently under investigation at the University of Virginia Cancer Center in the specific areas of neuro-oncology and prostate cancer as well as in the broad area of DNA damage response. As the first tier of investigations prove successful, we anticipate use in gynecologic, lung, and GI cancers and more generally. In addition to oncologic investigations, the SARRP will also facilitate research in the areas of immunology and cardiovascular diseases. The collaborative and communicative environment at UVA will ensure the rapid adoption of SARRP approach in a wide array of indications.